Research ArticleCancer

Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity

Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326ra20
DOI: 10.1126/scitranslmed.aad7785

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Killing cancer with a soft touch

Bleomycin is an effective chemotherapy drug that is used against multiple different types of cancer. Unfortunately, it often causes lung fibrosis or stiffening of the lungs, the severity of which correlates with the extent of exposure to the drug. To overcome this problem, Burgy et al. produced deglycobleomycin, a modified version of the drug that was just as effective against several different models of cancer but did not cause any detectable fibrosis in mouse lungs. If these findings are confirmed in clinical testing, deglycobleomycin could be a valuable addition to the therapeutic regimens for a variety of human cancers.

Abstract

Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin’s lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor–β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.

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